Specific Mutation

Key Eligibility Criteria:

Inclusion:
1. For Phase 1b: locally advanced, recurrent, or metastatic, incurable, and histologically or cytologically confirmed HR+/HER2- breast cancer by ASCO/CAP criteria (based on most recent assessment):
a) Must have received CDK4/6i in the adjuvant or metastatic setting, unless patient was unable or unwilling to receive standard of care CDK4/6i treatment; or must be able to receive it on protocol, AND,
b) Received no more than 1 prior line of therapy containing chemotherapy (including cytotoxic antibody-drug conjugates) given in the metastatic setting; AND,
c) Must have received no more than 3 lines of therapy in total for metastatic disease.
d) May have received a prior PI3Ka inhibitor

NOTE: If the patient progressed on the PI3K inhibitor a sample (tissue or liquid) must have been obtained following progression, or at study screening, to be analyzed at a CAP/CLIA-certified or equivalently accredited diagnostic laboratory, determine the resistance mutation(s) and Sponsor approval for study inclusion obtained. If the patient was intolerant to the drug, then mutational analysis and Sponsor approval are not required for enrollment.

Exclusion:
1. Has had tumor evaluated for PTEN and AKT and has known mutations or deletions in PTEN, or, activating mutations in AKT (E17K) determined at a CAP/CLIA-certified or equivalently accredited diagnostic laboratory (e.g., ISO15189-certified, in-house clinical testing).
2. Metaplastic breast cancer
3. Possible allergies to TOS-358 or excipients


For pre-screening, please contact: Message Basket: P VICC RESEARCH BREAST OHO

Drug(s)/Mechanism:
Belzutifan

Eligiblity information:
Cohort B1 specific inclusion criteria:

1. Have a diagnosis of VHL disease as determined by a germline test (documented germline VHL gene alteration) locally and/or clinical diagnosis, which can be made in the
following instances:
a. in a participant with a family history of VHL disease and at least one of the characteristic VHL-related tumors (eg, retinal HBs, CNS HBs, clear cell RCCs, pNETs, and endolymphatic sac tumors).
b. in the presence of 2 or more retinal or CNS HBs.
c. in the presence of 1 retinal or CNS HB, plus at least 1 of the characteristic VHLrelated visceral tumors, excluding renal and epididymal cysts.

2. Have at least 1 measurable PPGL or pNET per RECIST 1.1 by CT or MRI as assessed by local site investigator/radiology assessment and verified by BICR. BICR must verify the
presence of radiologically measurable disease per RECIST 1.1 for either PPGL or pNET for the participant to be eligible for the study.

3. For Cohort B1 participants with PPGL:
a. No pheochromocytoma >5 cm or paraganglioma >4 cm that requires immediate surgery.
b. Participants should have adequately controlled BP defined as BP 150/90 mm Hg and with no change in antihypertensive medications (for participants with concomitant hypertension) for at least 2 weeks prior to start of study treatment.
c. Metastatic or locally advanced, unresectable PPGL will be exclusionary.
d. Presence of concomitant VHL disease associated tumors is permitted as long as they do not require immediate surgery or intervention as applicable (see exclusion criteria #2d-2g).

4. For Cohort B1 participants with pNET:
a. No lesion(s) located in the head of the pancreas must be >2 cm that requires immediate surgery.
b. No lesion(s) located in the body or tail of the pancreas must be >3 cm that requires immediate surgery.
c. Locally advanced, unresectable or metastatic pNET will be exclusionary.
d. Presence of concomitant VHL disease associated tumors is permitted as long as they do not require immediate surgery or intervention as applicable (see exclusion criteria #2d-2g).

5. For Cohort B1 participants with RCC:
a. No lesion(s) must be >3 cm that requires immediate surgery.
b. Metastatic RCC will be exclusionary.
c. Presence of concomitant VHL disease associated tumors is permitted as long as they do not require immediate surgery or intervention as applicable (see exclusion criteria #2d-2g).

6. For Cohort D participants with advanced solid tumors with HIF-2A related genetic alterations:
a. Local test report documenting germline or somatic mutations in at least one of the HIF-2A related genes (HIF-2A/EPAS1, FH, SDHA, SDHB, SDHC, SDHD, SDHAF2, EGLN1, EGLN2, MDH2, ELOC/TCEB1).
b. Has locally advanced or metastatic solid tumor that is not amenable to surgery or curative intent treatment.
c. Participants must have progressed on/after standard therapy for advanced/metastatic disease. More than 3 prior therapies will not be allowed for this cohort in the advanced/metastatic setting.

For pre-screening, please contact: Message Basket: VICC RESEARCH REFERRALS/ELIGIBILITY

Key Eligibility Criteria:
Inclusion:
1. Patient has a histologically- or cytologically confirmed cancer that is advanced, recurrent, or metastatic with the following origins, and whose disease progressed on standard therapy and for whom there are no alternative therapies that may confer overall survival benefit:
a. For Patients in the Dose Escalation Part:
i. Platinum-resistant ovarian cancer (PROC)
1. Histologically diagnosed ovarian, fallopian tube, or primary peritoneal cancer, with predominantly high-grade (Grade 2 or 3) epithelial features (serous and clear cell)
2. Platinum resistant is defined as relapsed within 6 months after the last dose of platinum-based therapy
ii. Triple negative breast cancer (TNBC)
1. ER- and PR-negative with HER2 negative
2. HER2 negative is defined as one of the following: 0 or 1+ by IHC, or if IHC 2+, then in situ hybridization is negative per the ASCO-CAP HER2 guidelines
3. ER- and PR-negative is defined as < 10% of cells expressing hormonal receptors by IHC, as per standard guidelines
iii. Squamous cell carcinoma of the anus (SCCA)
1. Patient with locally advanced ineligible for surgery is allowed.
iv. Squamous cell carcinoma of the head and neck (SCCHN)
v. Non-small cell lung cancer (NSCLC: adenocarcinoma, large cell, and squamous cell carcinoma)
vi. Uterine serous cancer (recurrent or persistent)
b. For Patients in the Dose Expansion Part:
i. Cohort A: PROC (same as above)
ii. Cohort B: TNBC (same as above)
iii. Cohort C: SCCA (same as above)
2. For Dose Expansion only: Patient has measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and, if only one target lesion is present, has not received prior radiotherapy to the target lesion

Exclusion:
1. Patient has received prior treatment at any time with a cell cycle checkpoint inhibitor (eg, CHK1 and/or CHK2, WEE1, or ATR inhibition)


For pre-screening, please contact: Message Basket: VICC RESEARCH PHASE 1

Inclusion Criteria:
1. Patient must be deemed potentially eligible for a ComboMATCH Treatment Trial as assessed by the enrolling provider.
2. All patients must have sequencing results available from a National Cancer Institute (NCI) credentialed Designated Laboratory (DL)
3. Patients 18 years and older who have tumor amenable to minimal risk image-guided or direct vision biopsy and must be willing and able to undergo a tumor biopsy to obtain samples for research if the patient is to enroll in a ComboMATCH treatment trial OR
4. Patients 18 years and older who do not have disease that is biopsiable at minimal risk to the patient must confirm availability of an archival tumor tissue specimen for submission for research if the patient enrolls to a ComboMATCH Treatment Trial. This tumor tissue must meet the following criteria:
- Tissue must have been collected within 12 months prior to registration to the EAY191 Registration Trial
- Patient must not have had a Response Evaluation Criteria in Solid Tumors (RECIST) response (complete response [CR] or partial response [PR]) to any intervening therapy after collection of the tissue
- Formalin-fixed paraffin-embedded tumor tissue block(s) or slides must be available OR
5. Patients under 18 years old must confirm availability of an archival tumor tissue specimen for submission for research if patient enrolls to a ComboMATCH Treatment Trial. This tumor tissue must meet the following criteria:
- Formalin-fixed paraffin-embedded tumor tissue block(s) or slides must be available

* NOTE: See specific ComboMATCH Treatment Trial protocol for tissue collection and management instructions. Performance of the mandatory research biopsy or submission of pre-trial formalin-fixed paraffin-embedded (FFPE) and collection and submission of the blood specimens for the integrated studies will be performed under the consent authority of the specific treatment trial protocol to which the patient is registered. No procedures to collect specimens for research only are to be performed for patients registered to the EAY191 Registration Trial only

*NOTE: Each ComboMATCH Treatment Trial contains specific eligibility criteria. If patient is found to not be eligible for the assigned ComboMATCH Treatment Trial, indication of ineligibility will trigger re-evaluation and potential assignment to another Treatment Trial

Key Eligibility Criteria:
Inclusion Criteria:

1. Patient must have undergone RNA testing in a Clinical Laboratory Improvement Act (CLIA) environment or must submit archival tissue to determine RNA overexpression of ADC TOIs by the TARGET Assay. Patients who have high TOI RNA expression will have confirmation of TOI expression by CLIA IHC assay at MD Anderson Cancer Center (MDACC).

2. COHORT A: Patient must have high Trop-2 protein expression (IHC 2+ or 3+) excluding advanced colorectal cancer, urothelial cancer, head and neck cancer (Note: exceptions include patients with adenoid cystic cancer, salivary gland cancer, thyroid cancer, and parathyroid cancer, who are eligible), triple negative breast cancer (TNBC), HR-positive breast cancer, HER2-positive breast cancer, small cell lung cancer, NSCLC, and endometrial cancer

3. COHORT B: Patient must have high Nectin-4 protein expression (IHC 2+ or 3+) excluding advanced urothelial cancer, head and neck cancer (to include salivary gland cancer and adenoid cystic cancer), breast cancer, lung cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, prostate cancer, or penile cancer

4. COHORT C: Patient must have HER2 protein expression (IHC 2+ or 3+) excluding advanced breast cancer, non-small cell lung cancer (NSCLC), colorectal carcinoma (CRC), gastric cancer, or gastroesophageal junction (GEJ) cancer

Exclusion Criteria:

1. Active or chronic corneal disorder including, but not limited to, Sjogren's syndrome, Fuchs corneal dystrophy (requiring treatment), history of corneal transplantation, active herpetic keratitis, and/or active ocular conditions requiring ongoing treatment/monitoring such as wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, presence of papilledema, and acquired monocular vision
2. History of allergic reactions attributed to compounds of similar chemical or biologic composition to the ADCs used in the study
3. History of interstitial lung disease or pneumonitis requiring steroid therapy


For pre-screening, please contact: Individual research disease teams.

Key Eligibility Criteria:
Inclusion Criteria:
1. Histologic diagnosis of locally advanced or metastatic solid tumor malignancy (except CNS primary malignancy, for example, glioma), and where applicable, with an FGFR3 pathway alteration listed in Section 10.8, on molecular testing in tumor or blood sample that is deemed as actionable, as defined below per specified cohort.
2. Cohort B: Locally Advanced or Metastatic Urothelial Carcinoma
a. B1: LOXO-435 monotherapy- mUC, ≥2 prior regimens, including erdafitinib and EV
b. B2: LOXO-435 monotherapy- mUC, Qualifying FGFR3 alterations, ≥1 prior regimen, FGFR inhibitor naïve
c. B4: LOXO-435 monotherapy- mUC, ≥2 prior regimens, including erdafitinib; EV naïve
d. B5: LOXO-435 + Pembrolizumab + EV- mUC, Qualifying FGFR3 alterations, No prior systemic therapy
3. Cohort C: Locally Advanced or Metastatic Solid Tumors (Non-Urothelial Carcinoma)
a. C1: LOXO-435 monotherapy- Qualifying FGFR3 alterations, Progressed/intolerant to available standard therapies, FGFR inhibitor naïve
4. Have adequate tumor tissue sample available. Participants with inadequate tissue sample availability may still be considered for enrollment upon review

Exclusion Criteria:
1. Current evidence of corneal keratopathy or retinal disorder. Individuals with asymptomatic ophthalmic conditions may be eligible.
2. For Cohort B5 only, individuals with known uncontrolled diabetes.
3. For Cohorts B3 and B5 only, individuals with a history of non-infectious pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
4. Individuals with uncontrolled hypercalcemia <14 days to C1D1.


For pre-screening, please contact: Individual disease research teams.

Key Eligibility Criteria:

Inclusion Criteria:
1. Dose Expansion only:
a. Patients who have at least one measurable lesion, not previously irradiated and not chosen for biopsy during the study screening period, that can be accurately measured at baseline >/=10 mm in the longest diameter.
b. Mandatory provision of tumor tissue sample from a recent biopsy in a quantity sufficient to allow for analysis
c. All patients with biliary tract cancer or other solid tumor malignancies should have HER2 testing performed using a local laboratory
d. Cohort 1
i. Confirmed HER2-positive (IHC3+, or IHC2+ and ISH*+), locally advanced/unresectable or metastatic biliary tract cancer, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary adenocarcinoma (*ISH: FISH, SISH, or DISH)
ii. Failed or intolerant to at least 1 prior gemcitabine- and/or cisplatin-based therapy with/without immune checkpoint inhibitors as per available local standards
e. Cohort 2
i. Pathologically confirmed HER2-positive (IHC3+, or IHC2+ and ISH*+), locally advanced/unresectable or metastatic solid tumor malignancy other than breast and gastric or gastroesophageal junction adenocarcinoma and biliary tract cancer (*ISH: FISH, SISH, or DISH)
ii. Patients who have received all available standard therapies known to provide clinical benefit, and have no currently available treatment options due to disease progression, intolerance or other reasons

Exclusion Criteria:
1. History of (non-infectious) interstitial lung disease (ILD) or pneumonitis that required steroids, or any evidence of current ILD or pneumonitis.
2. Systemic steroid therapy (>10 mg daily prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.
3. Previous treatment with a 4-1BB/CD137-modulating agent.

For pre-screening, please contact: Your disease specific research team.

Key Eligibility Criteria:

Inclusion Criteria:
1. Histologically documented locally advanced and unresectable or metastatic NSCLC, PDAC, CRC, or other solid tumor with KRAS G12A, G12C, G12D, G12S, or G12V mutation
2. Measurable disease by RECIST v1.1
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1

Exclusion Criteria:
1. Malignancy within the last 2 years as specified in the protocol
2. Untreated brain metastases
3. Known hypersensitivity to BBO-11818 or its excipients

For pre-screening, please contact: VICC RESEARCH PHASE 1

Key Eligibility Criteria:

Inclusion Criteria:
1. Tumors must harbor a TP53 R175H variant mutation confirmed by an accredited laboratory-based test
2. Patients must be HLA-A*02:01 positive by central assay
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at the time of enrollment

Exclusion Criteria:
1. Patients with Li-Fraumeni syndrome or other known germline p53 R175H mutation
2. Patients who have received other p53 R175H-directed therapies
3. Any other primary malignancy within the 2 years prior to enrollment (except for non- melanoma skin cancer, carcinoma in situ (eg, cervix, bladder, breast) or prostate cancer in remission.
4. Known active central nervous system metastases and/or carcinomatous meningitis

For pre-screening, please contact: VICC RESEARCH PHASE 1

Key Eligibility Criteria:
Inclusion Criteria:
1. Subjects who have a histologically or cytologically documented metastatic or locally advanced solid tumor, for which standard of care (SoC) therapy does not exist, no longer provides benefit, or is not tolerated by the subject, or the subject has been assessed by the Investigator as not being suitable for SoC therapy.
Part B: Subjects must be diagnosed with one of the following solid tumors harboring specified genetic alterations based on a validated local test:
i. Melanoma Cohort(s):
1. Activating NRAS mutations& without known concomitant activating PIK3CA, AKT mutation or PTEN LOF
2. BRAF Class 2/3 mutations or fusions
ii. Non-Melanoma Cohorts:
1. Solid tumors with NRAS activating mutations& without known concomitant activating PIK3CA, AKT mutation or PTEN LOF
2. Solid tumors with KRAS activating mutations without known concomitant activating PIK3CA, AKT mutation of PTEN LOF
3. Solid tumors with BRAF Class 2/3 mutations or fusions
4. Glioma with BRAF Class 1, 2, or 3 mutations or fusions
2. Newly obtained or archived tumor tissue is required

Exclusion Criteria:
1. Current or history within 6 months of planned Cycle 1 Day 1 of pneumonitis or interstitial lung disease (ILD)
2. Part B: prior treatment with any MEK or BRAF inhibitor
3. A history or current evidence of significant retinal pathology leading to increased risk of retinal vein occlusion

For pre-screening, please contact: Message Basket: VICC RESEARCH PHASE 1

Key Eligibility Criteria:
Inclusion Criteria:
1. Have histologically or cytologically confirmed cancer diagnosis based on pathology report.
2. Willing to submit a pre-treatment (archival or fresh-tissue if no archival tissue is available) and on-treatment tissue sample. Additionally, during the dose-escalation portion and if appropriate in the expansion phase of the study, the Sponsor may modify subject enrolment into various cohorts that have not begun enrolling yet such that ENPP1 and/or cGAS baseline expression level in the subject's tumor must be available and may guide enrolment eligibility for the study.

Exclusion Criteria:
1. Subjects with evidence of rapid progression on prior therapy resulting in rapid clinical deterioration should be excluded from participation in the trial.
2. Uncontrolled tumor-related pain
3. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures.
4. History or any evidence of interstitial lung disease

For internal pre-screening, please contact: Message Basket: VICC RESEARCH PHASE 1